The object of the proposal is to gain further insight into the factors involved in the pathogenesis of hypertension. The investigations are divided into two parts: the first part is aimed at evaluating the role of the renin-angiotensin system, prostaglandins, adrenal mineralocorticoids, and catecholamines in certain types of hypertension. The effect of age, inheritance, inhibitors and humoral factors on the activity of the renin system will be evaluated. Extensive physiological and pharmacological studies will be carried out with an angiotensin II inhibitor, P113. The second part of the proposal involves in vitro studies. The regulation of aldosterone and other mineralocorticoid biosynthesis will be investigated at a cellular and subcellular level. The role of potassium, ACTH, growth hormone and a pituitary factor will be studied in isolated zona glomerulosa cells and an adrenal organ culture; pathways for generation of reducing equivalents for steroid hydroxylation will be evaluated in isolated adrenal mitochondria. Particular emphasis will be given to determining the properties and role of a newly recognized adrenal mitochondrial malic enzyme. Binding proteins involved in intracellular transport of steroid precursors will be investigated in subcellular fractions. One such binding protein pregnenolone appears to be the 3 beta-ol dehydrogenase and it will be further characterized.